Project Summary/Abstract All individuals with Parkinson?s disease (PD) are at risk for developing memory impairment and dementia, markedly increasing loss of employment, caregiver stress, increased cost to health systems, patient institutionalization, and decreased survival. There are no interventions available to prevent this devastating consequence of disease, making both PD Dementia (PDD) and the closely related Dementia with Lewy Bodies (DLB) a looming public health crisis. At autopsy, less than 40% of patients exhibit only Lewy body (LB) pathology, whereas 60-80% exhibit mixed LB and Alzheimer?s disease (LB/AD) pathology. Conversely, very few PD patients are thought to have AD co-pathology at clinical diagnosis. Unfortunately, we know little about when PD patients develop AD co-pathology, which creates a barrier to the development of effective therapies: PD patients without AD co-pathology would be ideal candidates for ?-synuclein targeted therapies, whereas PD patients with AD co- pathology likely would require combination therapy. Experiments proposed here take a significant step toward overcoming this barrier by identifying early Tau pathology in living patients relative to their cognitive progression. To perform these experiments, we will leverage the perfect co-registration of simultaneous PET/MRI to identify subtlely emerging Tau pathology in the medial temporal lobe. We will also determine whether the inflammatory amplifier Triggering Receptor Expressed on Myeloid Cells 2, or TREM2, is elevated in PD patients with Tau PET evidence of AD co-pathology, as is suggested by our preliminary data. Finally, we will determine the impact of AD co-pathology on cognitive progression and the onset of neuropsychiatric symptoms, such as psychosis. We will leverage the combined participants of the Pacific Udall Center and the Stanford Alzheimer?s disease Research Center, which provides a unique opportunity to study a well-characterized population of PD patients who are followed longitudinally with clinical assessments, biospecimen collection, and, ultimately, autopsy. A collaborative team of neuroscientists at Stanford University with training in Movement Disorders Neurology, Nuclear Medicine, Neuroimmunology, Biostatistics and Pathology will carry out these aims. The proposed studies are highly relevant to the mission of the National Plan to Address Alzheimer's Disease, which calls to improve dementia diagnosis and accelerate the development of treatments for Alzheimer's disease and related dementias, such as Parkinson?s disease dementia.